Compositions for nasal administration of pharmaceuticals

ABSTRACT

Compositions for nasal administration, which comprise a pharmaceutical, a physiologically active peptide, or a peptide-related compound, and as the carrier thereof, crystalline cellulose with a specific particle diameter and/or partially pregelatinized starch are provided. Such compositions improve the in vivo absorption efficiency of pharmaceuticals.

TECHNICAL FIELD

The present invention relates to pharmaceutical compositions that are administered via the nasal mucosa in granule form. Specifically, the present invention relates to granular compositions for nasal administration of physiologically active peptides such as insulin, or peptide-related compounds.

BACKGROUND ART

At present, insulin is clinically used as a treatment for diabetes in the form of an injectable formulation, and in most cases, it is self-administered by a comparatively simple subcutaneous injection. However, due to the characteristics of this type of injection formulation, the patient is required to self-administer one to four times a day before meals, for life. This troublesome procedure is one of the many problems associated with the treatment of diabetes. Besides insulin, many pharmaceutical peptides are also administered by injections, and there is an ongoing development of dosage forms for convenient administration.

Formulations for nasal administration, in particular, have been proposed to overcome the difficulties associated with administration. For example, a dosage form of insulin formulation, which uses crystalline cellulose as a base and has 90 wt % of particles in the diameter range of 20 to 150 μm, is described in Examined Published Japanese Patent Application No. (JP-B) Sho 62-42888. Considering that for this formulation, “physiologically active polypeptides are preferably water-soluble for nasal mucosal absorption,” the Example of this publication discloses that compositions having 90 wt % or more of particles with a diameter of 75 to 149 μm are obtained by: dissolving insulin in aqueous 0.1 N HCl and freeze-drying; mixing the thus-obtained soluble insulin powder with crystalline cellulose; and sifting.

In comparison with compositions in the above-mentioned JP-B Sho 62-42888, Unexamined Published Japanese Patent Application No. (JP-A) Hei 10-59841 (corresponding to EP-A1-943326) discloses compositions which demonstrate excellent nasal absorption and increased maximum blood concentration with highly hydrophilic pharmaceuticals, highly lipophilic pharmaceuticals, and high molecular weight peptides. According to this publication, the above-described effect can be achieved by actively using a water-absorbing and gel-forming base, such as hydroxypropylcellulose, in combination with a crystalline cellulose aggregate comprising particles with a diameter greater than 150 μm, which is contrary to what JP-B Sho 62-42888 suggests.

However, the present inventors are not aware of any information on the practical application of formulations for nasal administration, in particular, those for nasal administration of polypeptide hormones including insulin as described in these prior arts.

DISCLOSURE OF THE INVENTION

In contrast to what is suggested in the above-described JP-B Sho 62-42888 and JP-A Hei 10-59841, the present inventors discovered that compositions for nasal administration of polypeptide hormones or peptide-related compounds, which are prepared by using a partially pregelatinized starch powder having a specific particle diameter, alone or in combination, with a crystalline cellulose powder having a specific sieving particle diameter distribution of less than 150 μm, unexpectedly increase the absorbability and efficacy of pharmaceuticals significantly, compared to compositions in the prior art.

The present invention is based on this finding.

Accordingly, the present invention provides granular compositions for nasal administration comprising a powdered pharmaceutical and a substantially water-insoluble polysaccharide powder as a carrier thereof, wherein the pharmaceutical is selected from physiologically active peptides with a molecular weight of 30,000 or less, in particular, polypeptide hormones and peptide-related compounds, and more specifically, FK-506; and wherein the water-insoluble polysaccharide is at least one selected from: a crystalline cellulose powder with 85 wt % or more of the particles distributed over a partial or the entire sieving particle diameter range of 20 to 60 μm, and a partially pregelatinized starch powder with a mean particle diameter of 20 to 100 μm. Among such compositions, compositions comprising insulin as a pharmaceutical and only the above-described crystalline cellulose as a water-insoluble polysaccharide are also disclosed by the Applicant in JP-A 2001-204784.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph showing changes in the serum insulin concentrations after intranasal administration of each composition to cynomolgus monkeys.

FIG. 2 is a graph showing changes in the serum glucose concentrations after intranasal administration of each composition to cynomolgus monkeys.

FIG. 3 is a graph showing changes in the serum human growth hormone concentrations (the initial value is subtracted) after intranasal administration of each composition to cynomolgus monkeys.

FIG. 4 is a graph showing changes in the serum insulin concentrations after intranasal administration of each composition to cynomolgus monkeys.

FIG. 5 is a graph showing changes in the rate of reduction (%) in serum glucose concentrations after intranasal administration of each composition to cynomolgus monkeys.

FIG. 6 is a graph showing changes in the blood pharmaceutical concentrations after intranasal administration of each glucagon-comprising composition to cynomolgus monkeys.

FIG. 7 is a graph showing changes in the blood pharmaceutical concentrations after intranasal administration of each salmon calcitonin-comprising composition to cynomolgus monkeys.

FIG. 8 is a graph showing changes in the blood pharmaceutical concentrations after intranasal administration of each parathyroid hormone-comprising composition to cynomolgus monkeys.

BEST MODE FOR CARRYING OUT THE INVENTION

Pharmaceuticals of the present invention include physiologically active peptides with a molecular weight of 30,000 or less and peptide-related compounds; in particular, polypeptide hormone compounds and FK-506, that have higher in vivo absorption efficiency than nasal administration and are capable of exerting the efficacy in an effective manner, which are in accordance with the objectives of the present invention.

The physiologically active peptides with a molecular weight of 30,000 or less include linear and cyclic peptides, such as insulin, growth hormone, calcitonin, glucagon, glucagon-like peptide-1 (GLP-1), interferon, interleukin, erythropoietin, luteinizing hormone-releasing hormone, somatostatin, vasopressin, oxytocin, enkephalin, adrenocorticotropic hormone, growth hormone-releasing hormone, granulocyte colony formation-stimulating factor, parathyroid hormone, thyroid-stimulating hormone-releasing hormone, angiotensin, prolactin, luteinizing hormone, gastric inhibitory polypeptide (GIP), C-peptide, and cyclosporine. The term “peptide-related compounds” refers to physiologically active substances which comprise at least one peptide bond (amide or imide bond) in the molecular structure, and which are predominantly produced by microorganisms or organisms. A representative example of the peptide-related compounds is FK-506. These pharmaceuticals should not be limited by their origins, preparation methods, or the like. In addition, modified or altered pharmaceuticals can also be used so long as they have the desired efficacy. For example, the term “insulin” includes: human insulin, purified bovine insulin, purified porcine insulin, semi-synthesized human insulin, human iso-insulin, and such, that are currently in clinical use; and all genetically engineered human insulin and insulin modified therefrom, which have an activity equivalent to that of human insulin. Insulin of the present invention is preferably used in powder form. Preferably, the modified insulin powder is only slightly soluble in water or almost insoluble in water (specifically, 1 g of the corresponding insulin powder requires a solvent of 1,000 mL or more and less than 10,000 mL, or 10,000 mL or more to be solved; see, Japanese Pharmacopoeia 13^(th) Edition (Dai 13 Kaisei Nippon Yakkyoku Hou Kaisetu Sho), General Rule A-51). The above-mentioned insulins are slightly soluble or almost insoluble in water, and can be used as an insulin powder of the present invention. Similarly to insulin, other physiologically active peptides and peptide-related compounds that can be used are also not limited; however, the commercially available ones are preferred.

Powdered pharmaceuticals such as the above-described insulin must be a crystalline or non-crystalline fine powder, and must be finer than cellulose particles that constitute a crystalline cellulose powder, or partially pregelatinized starch particles described below. Generally, the surface or the surface microstructure (e.g., pores) of the above-described particles are required to have a particle size that allows the adhesion or inclusion of multiple pharmaceutical powders. Various commercially available pharmaceuticals in bulk powder can be employed directly or after being finely pulverized.

Generally, crystalline cellulose powders (or particles) used in the present invention can be obtained by: obtaining cc-cellulose as pulp from a fibrous plant, partially depolymerizing with an acid, and purifying the water-insoluble fraction. It is possible to use crystalline cellulose powders obtained from rayon filaments or such, as long as they meet the objectives of the present invention. Specifically, crystalline cellulose powders employed in the present invention can be obtained using, for example, the Avicel® series and its modified versions as described in JP-B Sho 39-12469, JP-13 Sho 56-38128, JP-B Sho 61-21201, and JP-B Hei 5-38732, by reducing the particle size using a high-speed impact pulverizer or an air flow-type pulverizer, as necessary; and/or finely pulverizing while increasing the bulk density; and size classifying or sifting to obtain an assembly of particles with the desired particle size.

The crystalline cellulose powder can usually be produced by depolymerization as described above, and its average degree of polymerization is not limited, as long as it meets the objectives of the present invention. A crystalline cellulose powder of the present invention can generally be selected from crystalline cellulose having an average polymerization degree of 15 to 400, preferably 20 to 250, and more preferably 30 to 50. The crystalline cellulose powders of the present invention are not limited, and crystalline cellulose powders that have a bulk density of 0.20 to 0.65 g/cm³, and preferably 0.22 to 0.40 g/cm³ can be utilized. These bulk density values are determined using the Scott Volumeter.

The critical criteria for selecting crystalline cellulose powders of the present invention are the size and distribution pattern of particles which constitute a crystalline cellulose powder. Specifically, it is necessary that approximately 85 wt % or more of the particles are in a partial or the entire sieving particle diameter range of 20 to 60 μm.

Hereinafter, the term “particle diameter” means sieving particle diameter, unless defined otherwise.

The partially pregelatinized starch powder (or particles) used as a second carrier in the present invention can be obtained from any starch using any method of partial pregelatinization, so long as it meets the objectives of the present invention. Without being limited thereto, physically denatured (i.e., heat-denatured) cornstarch is preferred. Such partially pregelatinized starch should be substantially water-insoluble. The term “substantially water-insoluble” means that 5% or less, and preferably 2.5% or less of the content is a water-soluble component at room temperature. The degree of swelling of the “partially pregelatinized” starch measured in pure water at about 20° C. is preferably adjusted to approximately 8 to 9 cm³/g.

Starch which has been size classified into a mean particle diameter of 20 to 100 μm, and preferably about 32 μm or less is used. A representative example of the partially pregelatinized starch, PCS® (degree of swelling: 8 to 9 cm³/g) supplied by Asahi Kasei Corporation, can be employed after the particle size classification, as necessary.

The term “partial or entire range” used to express a particle size distribution of the above-described powders means that in the example of crystalline cellulose, about 85 wt % or more of the crystalline cellulose particles have a particle diameter distribution within the entire range of 20 to 60 μm, or in a partial range thereof, for example, 20 to about 40 μm, 20 to about 55 μm, about 25 to 38 μm, about 25 to 53 μm, or about 38 to 53 μm. Specifically, commercially available Avicel® PH-F20 or PH-M15 can be used after size classification or as it is. Without being limited thereto, the crystalline cellulose powders preferably have a particle diameter distribution of:

10 wt % or fewer particles with a diameter smaller than 25 μm;

20 to 60 wt % particles with a diameter of 25 to 38 μm;

20 to 60 wt % particles with a diameter greater than 38 μm and smaller than or equal to 53 μm; and

the remaining particles having a diameter greater than 53 μm (total particles=100 wt %).

According to the present invention, the mixing ratio of powdered insulin, powdered glucagon, powdered calcitonin, parathyroid hormone, gastric inhibitory polypeptide (GIP), C-peptide, cyclosporine, or powdered FK-506, and a crystalline cellulose powder or partially pregelatinized starch, can be adjusted to 1:1 to 1:500 by weight, and more preferably 1:2 to 1:100 by weight.

To prepare compositions of the present invention by homogeneously mixing the above-mentioned powdered insulin with a crystalline cellulose aggregate, a commonly used device (for example, a blender or mixer) for homogeneously mixing a powdered pharmaceutical with a solid carrier can be used. Particles with a diameter smaller than 10 μm or greater than 100 μm may be subsequently removed; however, according to the present inventors' experience, such removal procedures are not needed.

Compositions of the present invention can comprise, in addition to the above-described components, other carriers or base materials, excipients, preservatives, antiseptics, absorption enhancers, or such, as long as they do not contradict the objectives of the present invention. For example, other carriers may include cellulose derivatives described in JP-A Hei 10-59841, such as hydroxypropylcellulose, hydroxypropylmethylcellulose, and methylcellulose. The absorption enhancers include the angelica described in U.S. Pat. No. 5,731,303, which is an essential oil, and its component, cyclopentadecanolide. When other carriers or absorption enhancers like these are used, the resulting compositions are preferably sifted so that more than 80% of the composition particles may have a particle diameter of 70 to 100 μm, preferably 20 to 60 μm.

Hereinbelow, the present invention will be specifically described with reference to examples of compositions for nasal absorption of physiologically active peptides according to the present invention, but it is not to be construed as being limited thereto. In the Examples, the compositions for nasal absorption were nasally administered in a single dose to cynomolgus monkeys (3 to 7 kg weight). Administration was conducted according to a method to administer each capsulated composition into the nasal cavity using an intranasal administration device (Jetlizer, Unisia Jecs Corporation).

EXAMPLE 1 Pharmacokinetics and Pharmacological Studies of Insulin in Cynomolgus Monkeys

Compositions for nasal absorption were prepared by thoroughly mixing in a mortar, 35 mg (insulin as originally provided) of a water-insoluble insulin powder (Intergen Company, 28.7 IU/mg) and 965 mg of crystalline cellulose (Avicel® PH-101 or Avicel® PH-F20, Asahi Kasei Corporation). Water-soluble insulin was prepared by dissolving 100 mg of a water-insoluble insulin powder in 1 mL of 0.1 N HCl, adding 40 mL of purified water thereto, and freeze-drying the resulting insulin solution. 36 mg of the water-soluble insulin powder (27.7 IU/mg) thus obtained was then mixed with 964 mg of the above-mentioned crystalline cellulose in a mortar to prepare compositions for nasal absorption. Each of the compositions for nasal absorption was administered nasally to cynomolgus monkeys (n=6), and then serum insulin and glucose concentrations were measured.

The serum insulin and glucose concentrations were measured using the EIA method (enzyme immunoassay) and the Glck·G-6-PDH method, respectively.

Pharmacokinetic parameters (mean±standard deviation) obtained using the serum insulin concentrations are shown in Table 1.

For each of the above-described compositions for nasal absorption, the time-course changes in serum insulin and glucose concentrations are shown in FIGS. 1 and 2, respectively. Raw data for FIG. 1 are shown in Tables 2 to 5.

TABLE 1 Dose Number of C_(max) T_(max) T_(1/2) AUC₀₋₄ Composition (IU/body) animals (μU/mL) (h) (h) (μU-h/mL) Avicel PH-F20 16 6 449.35 ± 183.66 0.33 ± 0.10 0.75 ± 0.33 361.55 ± 167.55 (Water-insoluble insulin) Avicel PH-F20 16 6 176.45 ± 143.46 0.28 ± 0.13 0.86 ± 0.44 157.33 ± 138.12 (Water-soluble insulin) Avicel PH-101 16 6 164.73 ± 70.76  0.33 ± 0.10 0.78 ± 0.26 129.78 ± 78.45  (Water-insoluble insulin) Avicel PH-101 16 6 153.95 ± 31.96  0.20 ± 0.07 0.96 ± 0.79 102.88 ± 24.16  (Water-soluble insulin) Note: C_(max): Maximum blood insulin concentration T_(max): Time to reach maximum blood concentration T_(1/2): Time to reduce the maximum blood concentration by half AUC₀₋₄: Total area under the blood concentration curve from 0 to 4 hours

TABLE 2 Administration of Avicel PH-F20 (water-insoluble insulin) (Time-course changes in insulin concentrations) Insulin (μU/mL) Animal No. 0 10 min 20 min 30 min 40 min 1 hr 2 hr 4 hr 1 60.8 225.2 239.6 194.6 149.8 66.9 10.0 2.3 2 24.1 349.0 632.0 529.5 412.5 181.2 45.4 15.9 3 18.8 220.3 708.0 663.0 471.5 201.4 35.6 3.5 4 2.9 124.4 274.5 307.0 224.0 61.4 16.6 5.4 5 76.1 287.0 413.5 384.5 214.0 105.5 20.8 6.4 6 20.4 396.0 370.0 211.0 95.9 24.9 9.2 4.8 Average 33.85 266.98 439.60 381.60 261.28 106.88 22.93 6.38 Standard deviation 28.18 98.01 190.70 184.77 148.64 70.49 14.60 4.88

TABLE 3 Administration of Avicel PH-F20 (water-soluble insulin) (Time-course changes in insulin concentrations) Insulin (μU/mL) Animal No. 0 10 min 20 min 30 min 40 min 1 hr 2 hr 4 hr 1 3.8 385.0 434.0 392.0 322.0 123.2 18.4 2.3 2 7.0 72.6 58.6 32.2 28.5 14.0 5.7 6.7 3 3.4 71.4 98.2 116.3 85.7 29.4 11.3 1.3 4 3.2 51.2 32.0 18.4 10.8 5.6 3.0 7.9 5 2.8 228.1 247.0 235.6 171.8 92.4 14.6 4.8 6 2.7 137.6 108.0 65.7 37.9 19.1 14.0 1.3 Average 3.82 157.65 162.97 143.37 109.45 47.28 11.17 4.05 Standard deviation 1.61 128.89 152.17 144.96 119.19 48.49 5.81 2.85

TABLE 4 Administration of Avicel PH-101 (water-insoluble insulin) (Time-course changes in insulin concentrations) Insulin (μU/mL) Animal No. 0 10 min 20 min 30 min 40 min 1 hr 2 hr 4 hr 1 8.2 80.4 63.9 32.0 19.4 8.8 3.4 3.3 2 5.2 83.0 162.8 125.6 96.2 44.7 9.7 2.7 3 12.7 159.6 265.0 265.5 211.4 103.0 16.8 5.1 4 2.7 113.1 182.2 160.3 73.5 41.0 4.8 3.2 5 4.5 62.6 89.8 40.8 23.8 13.1 5.1 3.3 6 5.4 184.7 207.7 120.2 56.5 35.7 5.6 5.5 Average 6.45 113.90 161.90 124.07 80.13 41.05 7.57 3.85 Standard deviation 3.54 48.60 74.76 85.72 70.65 33.77 5.00 1.15

TABLE 5 Administration of Avicel PH-101 (water-soluble insulin) (Time-course changes in insulin concentrations) Insulin (μU/mL) Animal No. 0 10 min 20 min 30 min 40 min 1 hr 2 hr 4 hr 1 0.4 176.6 172.3 88.0 58.7 32.6 10.9 3.6 2 2.0 127.9 118.3 73.2 52.3 21.4 4.2 1.4 3 1.8 123.2 160.2 110.3 109.2 42.7 6.7 0.6 4 8.6 153.4 151.6 76.2 35.9 16.1 2.0 2.2 5 6.0 108.8 71.9 69.0 35.5 17.3 5.0 1.9 6 0.9 196.8 111.5 73.5 38.5 17.6 9.4 7.2 Average 3.28 147.78 130.97 81.70 55.02 24.62 6.37 2.82 Standard deviation 3.27 34.01 37.46 15.42 28.20 10.74 3.33 2.37

Table 1 shows that when 16 IU/body of insulin was intranasally administered, water-insoluble insulin revealed the greatest insulin absorbability with Avicel® PH-F20, followed by water-soluble insulin with Avicel® PH-F20, water-insoluble insulin with Avicel® PH-101, and water-soluble insulin with Avicel® PH-101. In other words, compositions of water-insoluble insulin plus Avicel® PH-F20, water-insoluble insulin plus Avicel® PH-101, and water-soluble insulin plus Avicel® PH-F20, were found to achieve higher insulin absorbability than the water-soluble insulin plus Avicel® PH-101 composition.

EXAMPLE 2 Pharmacokinetics of Human Growth Hormone in Cynomolgus Monkeys

Compositions for nasal administration were prepared by thoroughly mixing in a mortar, 17.5 mg of powdered human growth hormone (comprising 14.3% human growth hormone; Wako Pure Chemical Industries, Ltd.) and 62.5 mg of crystalline cellulose (Avicel® PH-F20; Asahi Kasei Corporation). The control composition for nasal administration, which comprises crystalline cellulose (Avicel® PH-101; Asahi Kasei Corporation) as a carrier, was also prepared in the same manner. Either of the compositions was nasally administered in a single dose to cynomolgus monkeys (n=3), and then the serum concentrations of human growth hormone were measured.

The human growth hormone concentrations were measured using the EIA method (enzyme immunoassay).

Pharmacokinetic parameters (mean±standard deviation) obtained using the human growth hormone concentrations (the initial value is subtracted) are shown in Table 6.

Time-course changes in the human growth hormone concentrations (the initial value is subtracted) are shown in FIG. 3. Raw data for FIG. 3 are shown in Tables 7 and 8 (Pharmacokinetic parameters have the same meanings as in Table 1).

TABLE 6 Dose Number of C_(max) T_(max) T_(1/2) AUC_(0.3) Composition (mg/body) animals (ng/mL) (h) (h) (ng · h/mL) Human growth hormone 0.5 3 18.97 ± 6.60  0.75 ± 0.43 0.56 ± 0.24 32.00 ± 13.02 (Avicel PH-F20) Human growth hormone 0.5 3 14.90 ± 10.05 0.19 ± 0.10 0.90 ± 0.85 18.03 ± 17.54 (Avicel PH-101)

TABLE 7 Administration of human growth hormone (Avicel PH-F20) (Time-course changes in human growth hormone concentrations) Human growth hormone (ng/mL) (the initial value is subtracted) Animal No. 0 5 min 15 min 30 min 45 min 1 hr 2 hr 3 hr 1 0.0 3.2 5.8 9.1 8.9 11.5 5.6 0.1 2 0.0 19.1 21.4 20.0 18.9 19.9 6.1 1.4 3 0.0 19.6 21.8 23.2 23.4 24.0 9.7 3.3 Average 0.00 13.97 16.33 17.43 17.07 18.47 7.13 0.67 Standard deviation 0.00 9.33 9.12 7.39 7.42 6.37 2.24 2.40

TABLE 8 Administration of human growth hormone (Avicel PH-101) (Time-course changes in human growth hormone concentrations) Human growth hormone (ng/mL) (the initial value is subtracted) Animal No. 0 5 min 15 min 30 min 45 min 1 hr 2 hr 3 hr 1 0.0 8.6 9.2 7.5 7.2 9.0 4.4 7.4 2 0.0 26.3 26.5 24.7 21.1 16.9 5.0 2.5 3 0.0 9.0 6.0 1.3 1.5 0.5 2.1 4.9 Average 0.00 14.63 13.90 11.17 8.98 8.47 2.43 3.27 Standard deviation 0.00 10.11 11.03 12.12 11.40 8.71 3.94 5.15

In Table 6, the human growth hormone compositions for nasal administration comprising Avicel® PH-F20 as a carrier showed an absorbability clearly higher than using Avicel® PH-101 as a carrier (see also FIG. 3).

EXAMPLE 3 Studies of Pharmacological Effects of Insulin in Cynomolgus Monkeys using Pregelatinized Starch as a Carrier or an Additive

The composition (hereinafter F20) comprising Avicel® PH-F20 as a carrier was compared to the following compositions, using a water-insoluble insulin powder (Intergen Company; 28.7 IU/mg).

An insulin composition (hereinafter in-PCS) was prepared by thoroughly mixing in a mortar, 35 mg of water-insoluble insulin powder (Intergen Company; 28.7 IU/mg) (insulin as originally provided) and 965 mg of partially pregelatinized starch (PCS®, Asahi Kasei Corporation) as a carrier, which has been size classified into 32 μm or less (hereinafter s-PCS).

A second composition (hereinafter in-PCS+F20 (1:1)) was prepared by: thoroughly mixing in a mortar, 35 mg of water-insoluble insulin powder (Intergen Company; 28.7 IU/mg) (insulin as originally provided) and 965 mg of crystalline cellulose (Avicel® PH-F20, Asahi Kasei Corporation), to prepare an insulin composition (hereinafter F20); and then mixing in-PCS with F20 at a ratio of 1:1.

Additional compositions were prepared by adding 1% or 10% s-PCS to F20 (hereinafter, F20+1% s-PCS and F20+10% s-PCS).

Each of these compositions was nasally administered to cynomolgus monkeys (n=3 to 6) at 16 IU insulin per body. Serum insulin and glucose concentrations were measured following the administration of each composition.

Insulin and glucose concentrations were measured using the EIA method (enzyme immunoassay) and the Glck·G-6-PDH method, respectively.

Table 9 shows pharmacokinetic parameters (mean±standard deviation) obtained using the serum insulin concentrations, and pharmacological parameters obtained using the serum glucose concentrations.

FIGS. 4 and 5 show, respectively, changes in the serum insulin concentrations and the rate of reduction (%) of the serum glucose concentrations over time, using the above-described compositions for nasal absorption. Raw data for FIG. 5 are shown in Tables 10 to 14.

TABLE 9 in-PCS + F20 F20 + 1% F20 + 10% Composition F20 in-PCS (1:1) s-PCS s-PCS Administration route Nasal Nasal Nasal Nasal Nasal Number of animals 6 6 6 3 3 Dose (IU/body) 16 16 16 16 16 C_(max) (μU/mL) 449.35 ± 183.66 120.63 ± 34.59 210.02 ± 60.05  402.33 ± 185.28 269.97 ± 168.02 T_(max) (h) 0.33 ± 0.10  0.44 ± 0.09 0.31 ± 0.12 0.39 ± 0.10 0.33 ± 0.00 T_(1/2) (h) 0.75 ± 0.33  0.98 ± 0.20 0.70 ± 0.24 0.61 ± 0.13 0.65 ± 0.21 AUC_(0.4) (μU · h/mL) 361.55 ± 167.55 152.17 ± 59.27 207.26 ± 119.42 334.21 ± 146.05 214.89 ± 102.36 AAC_(0.4) (% · h) 193.25 ± 69.31  236.89 ± 48.97 195.89 ± 104.79 119.21 ± 102.50 248.33 ± 26.57  AAC_(0.4)/AUC_(0.4) 0.5 1.6 0.9 0.4 1.2

TABLE 10 Administration of F20 (Time-course changes in glucose concentrations) Glucose (mg/dL) Animal No. 0 10 min 20 min 30 min 40 min 1 hr 2 hr 4 hr 1 85.07 77.95 53.43 44.40 19.23 13.26 36.26 50.58 2 96.47 117.31 77.69 68.04 57.48 24.21 17.95 40.33 3 80.62 105.72 64.02 31.01 18.51 21.54 34.60 44.29 4 68.43 87.74 66.95 33.74 28.02 16.26 13.87 14.10 5 77.97 93.67 68.23 47.85 33.50 31.68 56.55 73.31 6 76.74 75.08 57.93 33.13 31.89 36.97 55.52 72.92 Average 80.88 92.91 64.71 43.03 31.44 23.99 35.79 50.92 Standard deviation 9.39 16.30 8.43 14.00 14.22 9.04 18.00 22.76 Reduction (%) Mean 100.00 115.09 80.60 52.51 38.44 29.99 44.88 62.93 standard deviation 0.00 16.41 11.74 11.82 13.96 12.04 23.76 29.55

TABLE 11 Administration of in-PCS (Time-course changes in glucose concentration) Glucose (mg/dL) Animal No. 0 10 min 20 min 30 min 40 min 1 hr 2 hr 4 hr 1 90.40 165.10 157.59 123.66 82.02 45.60 32.53 44.50 2 112.71 126.08 103.15 96.35 85.86 56.69 27.61 54.72 3 106.98 148.35 75.27 32.50 10.67 15.25 23.91 108.31 4 101.65 116.66 95.01 67.87 41.65 17.60 16.67 42.53 5 108.78 112.18 89.90 51.98 20.33 24.83 27.01 63.03 6 119.28 65.52 32.44 20.28 18.26 19.11 12.56 28.89 Average 106.63 122.32 92.23 65.44 43.13 29.85 23.38 57.00 Standard deviation 9.90 34.30 40.66 39.13 33.26 17.16 7.45 27.68 Reduction (%) Mean 100.00 117.66 89.92 64.03 41.98 28.53 22.43 53.84 standard deviation 0.00 42.07 47.98 43.29 34.13 17.16 8.62 25.82

TABLE 12 Administration of in-PCS + F20 (1:1) (Time-course changes in glucose concentration) Glucose (mg/dL) Animal No. 0 10 min 20 min 30 min 40 min 1 hr 2 hr 4 hr 1 57.70 48.72 17.64 21.62 13.59 23.72 33.70 53.75 2 113.51 114.41 51.53 10.60 18.88 10.35 6.25 23.43 3 98.94 91.61 42.72 16.58 10.46 7.61 8.64 27.58 4 68.39 78.29 54.11 33.32 23.81 20.65 34.66 56.91 5 64.47 58.15 22.80 15.99 12.87 18.95 39.38 63.00 6 65.82 76.47 40.22 39.50 36.38 44.95 61.37 62.54 Average 78.14 77.94 38.17 22.94 19.33 21.04 30.67 47.87 Standard deviation 22.52 23.51 14.93 11.18 9.64 13.25 20.62 17.72 Reduction (%) Mean 100.00 99.78 49.12 32.85 26.80 30.97 46.27 69.60 standard deviation 0.00 13.15 18.03 19.43 16.12 22.44 33.65 35.54

TABLE 13 Administration of F20 + 1% s-PCS (Time-course changes in glucose concentration) Glucose (mg/dL) Animal No. 0 10 min 20 min 30 min 40 min 1 hr 2 hr 4 hr 1 60.76 86.82 59.55 42.98 36.05 47.83 43.82 53.42 2 87.43 120.23 53.89 36.08 25.08 26.81 20.35 52.92 3 61.10 120.83 81.10 44.00 34.30 39.34 64.89 61.57 Average 69.76 109.29 64.85 41.02 31.81 37.99 43.02 55.97 Standard deviation 15.30 19.46 14.36 4.31 5.89 10.57 22.28 4.86 Reduction (%) Mean 100.00 159.39 97.46 61.34 48.05 57.92 67.20 83.07 standard deviation 0.00 33.34 35.55 17.39 16.84 24.67 41.68 20.55

TABLE 14 Administration of F20 + 10% s-PCS (Time-course changes in glucose concentrations) Glucose (mg/dL) Animal No. 0 10 min 20 min 30 min 40 min 1 hr 2 hr 4 hr 1 74.20 42.87 28.71 20.50 22.62 20.57 16.10 38.09 2 94.62 136.76 94.11 63.94 51.20 35.04 21.33 54.25 3 113.47 82.83 38.09 23.77 19.26 6.19 30.21 64.00 Average 94.10 87.49 53.64 36.07 31.03 20.60 22.55 52.11 Standard deviation 19.64 47.12 35.36 24.17 17.55 14.43 7.13 13.09 Reduction (%) Mean 100.00 91.77 57.24 38.72 33.86 23.40 23.62 55.02 standard deviation 0.00 46.33 36.65 25.22 18.80 16.22 2.63 3.23

As shown in Table 9, in-PCS, in-PCS+F20 (1:1), and F20+10% s-PCS have AAC_(0.4)/AUC_(0.4) values between 0.9 and 1.6, which are significantly higher than that of F20 (0.5), suggesting that compositions using PCS as a carrier or an additive can reduce blood glucose more efficiently, but have lower insulin absorbability than compositions using F20 as a carrier (see also FIGS. 4 and 5).

EXAMPLES 4 TO 6 Pharmacokinetics Studies of Glucagon, Salmon Calcitonin, and Parathyroid Hormone in Cynomolgus Monkeys

Compositions for nasal administration were prepared by thoroughly mixing in a mortar, crystalline cellulose (Asahi Kasei, Corporation; Avicel® PH-F20) and as a physiologically active peptide, 0.6 mg of glucagon (derived from swine; Bachem), 100 IU of salmon calcitonin (Bachem), or 30 μg of parathyroid hormone (1-34, Penisula Laboratories Inc.), for every 16 mg of the composition. The control composition for nasal administration was prepared using crystalline cellulose (Asahi Kasei Corporation; Avicel® PH-101) as a carrier in the same manner. Each of the above-described compositions was nasally administered in a single dose to a cynomolgus monkey (n=1), and then the concentrations of glucagon, salmon calcitonin, and parathyroid hormone in blood were measured.

The blood concentrations of glucagon, salmon calcitonin, and parathyroid hormone were measured using the RIA double antibody method.

Time-course changes in the blood concentrations of glucagon, salmon calcitonin, and parathyroid hormone are shown in FIGS. 6, 7, and 8, respectively. Raw data for FIGS. 6, 7, and 8 are shown in Tables 15, 16, and 17.

TABLE 15 Administration of glucagon (Time-course changes in glucagon concentrations) Animal Glucagon (pg/mL) (the initial value is subtracted) No. 0 5 min 15 min 30 min 45 min 1 hr 2 hr 3 hr Avicel 0 49 358 400 396 350 150 10 PH-F20 1 Avicel 0 35 347 303 250 99 55 −5 PH-101 1

TABLE 16 Administration of salmon calcitonin (Time-course changes in salmon calcitonin concentrations) Salmon calcitonin (pg/mL) (the initial value is subtracted) Animal No. 0 5 min 15 min 30 min 45 min 1 hr 2 hr 3 hr Avicel PH-F20 0.00 200.31 555.23 504.01 456.21 443.86 198.11 4.53 1 Avicel PH-101 0.00 97.22 509.56 356.64 203.77 112.39 99.19 4.76 1

TABLE 17 Administration of parathyroid hormone (Time-course changes in parathyroid hormone concentrations) Animal Parathyroid hormone (pg/mL) (the initial value is subtracted) No. 0 5 min 15 min 30 min 45 min 1 hr 2 hr 3 hr Avicel 0.00 34.9 134.6 129.6 131.9 127.8 77.3 5.1 PH-F20 1 Avicel 0.00 29.6 128.4 89.3 53.8 45.3 20.3 2.9 PH-101 1

The glucagon-, salmon calcitonin-, and parathyroid hormone-comprising compositions for nasal administration, respectively shown in FIGS. 6, 7, and 8, which use Avicel® PH-F20 as a carrier, have an absorbability clearly higher than those using Avicel® PH-101 as a carrier.

INDUSTRIAL APPLICABILITY

The present invention provides compositions for nasal administration which are capable of efficiently increasing the blood concentration of pharmaceuticals. Thus, compositions of the present invention can be utilized in the medical field including the pharmaceutical industry. 

1. A method of intranasally administering a physiologically active peptide or peptide-related compound to a primate, the method comprising: intranasally administering to the primate a powdery pharmaceutical composition comprising: the physiologically active peptide or peptide-related compound; and a carrier, wherein: the physiologically active peptide or peptide-related compound has a molecular weight of 30,000 or less, and the carrier comprises crystalline cellulose particles having a mean sieving particle diameter of about 60 μm or less.
 2. The method of claim 1, wherein the physiologically active peptide or peptide-related compound is selected from the group consisting of insulin, human growth hormone, calcitonin, glucagon, parathyroid hormone, parathyroid hormone (1-34), glucagon-like peptide-1, interferon, interleukin, erythropoietin, luteinizing hormone-releasing hormone, somatostatin, vasopressin, oxytocin, enkephalin, adrenocorticotropic hormone, growth hormone-releasing hormone, granulocyte colony formation-stimulating factor, parathyroid hormone, thyroid-stimulating hormone-releasing hormone, angiotensin, prolactin, luteinizing hormone, gastric inhibitory polypeptide (GIP), C-peptide, cyclosporine, and FK-506.
 3. The method of claim 1, wherein the powdery pharmaceutical composition comprises insulin.
 4. The method of claim 1, wherein the powdery pharmaceutical composition comprises human growth hormone.
 5. The method of claim 1, wherein the powdery pharmaceutical composition comprises glucagon.
 6. The method of claim 1, wherein the powdery pharmaceutical composition comprises glucagon-like peptide-1.
 7. The method of claim 1, wherein the powdery pharmaceutical composition comprises calcitonin.
 8. The method of claim 1, wherein the powdery pharmaceutical composition comprises parathyroid hormone.
 9. The method of claim 1, wherein the powdery pharmaceutical composition comprises parathyroid hormone (1-34).
 10. The method of claim 1, wherein the powdery pharmaceutical composition comprises luteinizing hormone-releasing hormone.
 11. The method of claim 1, wherein the physiologically active peptide or peptide-related compound is in the form of a powder finer than the crystalline cellulose particles.
 12. The method of claim 1, wherein 85 wt % or more of the crystalline cellulose particles are distributed over a sieving particle diameter range of about 20 to 60 μm.
 13. The method of claim 1, wherein the crystalline cellulose particles have a sieving particle diameter distribution of: about 10 wt % or fewer particles with a diameter smaller than about 25 μm; about 20 to 60 wt % particles with a diameter of about 25 to 38 μm; about 20 to 60 wt % particles with a diameter greater than about 38 μm and smaller than or equal to about 53 μm; and the remaining particles having a diameter greater than about 53 μm but up to about 60 μm or less.
 14. The method of claim 1, wherein the crystalline cellulose particles have an average polymerization degree of about 20 to
 250. 15. The method of claim 1, wherein the crystalline cellulose particles have an average polymerization degree of about 30 to
 50. 16. The method of claim 1, wherein the crystalline cellulose particles have a bulk density of about 0.22 to 0.65 g/cm³.
 17. The method of claim 1, wherein the crystalline cellulose particles have a bulk density of about 0.22 to 0.40 g/cm³.
 18. The method of claim 1, wherein the crystalline cellulose particles have a bulk density of about 0.22 g/cm³. 